“Inflamm-Aging”: Inflammatory Signals in the Brain Regulate the Lifespan of Mice
The hypothalamus is located at the base of the brain and in adult humans, it has a volume of only 4cm3, less than half a percent of the total adult human brain volume. Despite its small size, the hypothalamus is one of the most important control centers in our brain because it functions as the major interface between two regulatory systems in our body: The nervous system and the endocrine (hormonal) system. It consists of many subunits (nuclei) which continuously sense inputs and then respond to these inputs by releasing neurotransmitters or hormones that regulate a broad range of vital functions, such as our metabolism, appetite, thirst, reproduction, temperature and even our internal timing system, the circadian clock. As if this huge workload wasn't enough, researchers have now uncovered an additional role for the hypothalamus: regulating lifespan.
The recent paper "Hypothalamic programming of systemic ageing involving IKK-β,NF-κB and GnRH" published in the journal Nature (published online May 1, 2013) by Guo Zhang and colleagues at the Albert Einstein College of Medicine in New York used elegant genetic mouse models to either continuously activate or continuously suppress the function of the NF-κB protein in the hypothalamus. This protein is a key transcription factor which is found in most organs and tissues and turns on genes in response to an inflammatory stimulus. The researchers were thus able to artificially create an internal scenario in which the hypothalamus was receiving a continuous "inflammation on" or "inflammation off" input without having to provide any external infectious or inflammatory agents. The results were quite striking. Continuous activation of the inflammatory NF-κB pathway in the hypothalamus resulted in a reduction of overall lifespan in the mice, but it also resulted in a loss of muscle mass, bone mass, and cognitive function - the mice showed signs of accelerated aging. An even more remarkable finding was that continuous suppression of the inflammatory pathway extended the lifespan of the mice when compared to their littermates that did not undergo any genetic modifications. Not only did these mice live longer (median lifespan increased by 23%), but they also exhibited significantly less physical and cognitive decline than regular mice!
To investigate the mechanism by which the suppression of inflammatory signals could result in such a profound increase in longevity and functional capacity, the researchers studied Gonadotropin Releasing Hormone (GnRH), one of the major hormones released by the hypothalamus which in turn regulates the release of reproductive hormones. They found that aging or inflammatory activation indeed suppressed GnRH release, whereas inhibition of the inflammatory signaling was able to restore GnRH levels. More importantly, simply injecting the mice with GnRH was able to prevent the physical and cognitive decline in the aging mice. How the injections of GnRH were able to restore muscle mass and even cognitive function was not evaluated in the study, but the researchers did observe that the brain showed increased evidence of neuron growth, which could explain the anti-aging effects of GnRH.
This paper is not the first to link inflammation to aging, but it is the first to show that localized inflammation signals in the hypothalamus can have such a profound effect on the lifespan of mice and it is also the first to propose that suppression of GnRH may be the reason for this inflammation-aging link. As with all important scientific papers, this study raises more questions than it answers. Is GnRH not just a regulator of sex hormones, but does it also exert effects on neurons and muscle cells that are independent of its role as a regulator of reproductive hormones? The mice with prolonged life-spans were all studied in a laboratory setting and thus not exposed to infectious agents that mice (or humans, for that matter) living in the wild commonly encounter. Would suppression of the NF-κB pathway in the hypothalamus possibly compromise their ability to fend off infections or other natural forms of inflammation? It is also not clear whether the GnRH link would apply to all mammals such humans, since aging female primates have higher, (not lower!) GnRH levels. These are all questions that lie beyond the scope of this paper and they need to be addressed in future papers.
However, there are some major limitations of this study and the proposed new hypothalamus-inflammation-GnRH-aging model. First, there is one rather obvious experiment that is missing. The researchers showed that manipulating NF-κB in the hypothalamus can have a major effect on the lifespan and the cognitive as well as physical function, but for some reason the researchers did not show the results from a rather simple experiment: Does GnRH alone extend the lifespan? If GnRH were really the main pathway by which the hypothalamus regulates aging, than giving GnRH ought to have extended the lifespan of the mice.
A second limitation of the paper is that it does not distinguish between general functional decline versus decreased regeneration. Biological aging is characterized by a gradual functional decline over time, but this is due to a combination of at least two parallel processes. Existing cells and tissues accumulate damaged and become dysfunctional and regenerative stem cells or progenitor cells become exhausted and cannot keep up with the repair. This study does not assess whether increased NF-κB activation in the hypothalamus causes more cellular dysfunction, whether it merely inhibits the regenerative repair process or whether it affects both. The researchers did not perform assessments of cellular aging, such as measuring the expression levels of the cellular aging regulator p16 or quantify oxidative stress. Therefore, it is unclear whether NF-κB activation in the hypothalamus had any impact on the cellular aging (senescence) program in the brain, muscles or elsewhere in the body.
Another key limitation is that the hypothalamus has so many functions other than GnRH release, which could all contribute to aging and changes in the lifespan of the mice. The authors themselves have previously published that NF-κB in the hypothalamus regulates the link between obesity and high blood pressure and multiple other groups have already shown that the hypothalamus may affect aging via its role in metabolic regulation. Unfortunately, the current study glosses over the potential role of metabolism and high blood pressure, which could explain the observed longevity effects and instead just focuses on the more provocative but less substantiated idea of GnRH as the aging regulator.
Due to these limitations, we still have to await additional studies that confirm the role of GnRH as the target for NF-κB activation in the hypothalamus and this link between inflammation, aging and the hypothalamus.
We should also remember that biological aging is just one aspect of aging. As André Maurois once wrote, "Old age is far more than white hair, wrinkles, the feeling that it is too late and the game finished, that the stage belongs to the rising generations. The true evil is not the weakening of the body, but the indifference of the soul."
Image credit: A GIF depicting the Hypothalamus "BodyParts3D", © The Database Center for Life Science - Creative Commons license via Wikimedia Commons, Painting by John Haberle (1856-1933) - Time and Eternity, via Wikimedia Commons
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, & Cai D (2013). Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature, 497 (7448), 211-216 PMID: 23636330